Digital direct reading colorimeter

ABSTRACT

A combined blood constituent and prothrombin time analyzer is provided in which a plurality of removable and replaceable circuit modules are utilized to program the analyzer for appropriate light wavelength, reagent blank offset, scale factos and calibration parameters and which is self referencing to predetermined standards such that the results derived are all normalized for readout on a common digital readout device. The entire analyzer is contained in a compact console which includes controlled incubated storage for blood test samples together with insertion cavities for both constituent concentration and prothrombin time analysis. The results of each analysis are so normalized by the blood analyzer that a common digital counter can be used to convert these results to a numerical readout presentable on a common readout device and said results are substantially instantaneously displayed subsequent to initiation of any given test in the analyzer.

United States Patent [1 1 Kiess et al.

Sept. 3, 1974 DIGITAL DIRECT READING COLORIMETER Filed: Nov. 30, 1972 Appl. No.: 310,771

Related US. Application Data Continuation-in-part of Ser. Nos. 1 13,881, Feb. 9, 1971, Pat. No. 3,676,007, and SenNo. 224,457, Feb. 8, 1972, Pat. No. 3,676,007, said Ser. No. 224,457, is a continuation-in-part of Ser. No. 1 13,881, which is a continuation-in-part of Ser. No. 692,525, Dec. 21, 1967, Pat. No. 3,561,878.

References Cited UNITED STATES PATENTS 9/1970 Bowker 356/200 7/1971 Schmitz 356/39 X 11/1971 Wheable 324/115 12/1972 Rapoza et a1. 356/184 OTHER PUBLICATIONS Enke, Analytical Chemistry, Vol. 43, No. 1, January,

1971, pp. 69A73A, 75A-78A and 80A.

Williard et al., Instrumental Methods of Analysis, D. van Nostrand, New York, (1965), Title page plus pp. 92-93.

Primary ExaminerRonald L. Wibert Assistant ExaminerR. J. Webster [5 7 ABSTRACT A combined blood constituent and prothrombin time analyzer is provided in which a plurality of removable and replaceable circuit modules are utilized to program the analyzer for appropriate light wavelength, reagent blank offset, scale factos and calibration parameters and which is self referencing to predetermined standards such that the results derived are all normalized for readout on a common digital readout device. The entire analyzer is contained in a compact console which includes controlled incubated storage for blood test samples together with insertion cavities for both constituent concentration and prothrombin time analysis. The results of each analysis are so normalized by the blood analyzer that a common digital counter can be used to convert these results to a numerical readout presentable on a common readout device and said results are substantially instantaneously displayed subsequent to initiation of any given test in the analyzer.

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saw I as or 11 DIGITAL DIRECT READING COLORIMETER This application is a continuation-in-part of copending application Ser. No. 113,881, filed Feb. 9, 1971, and now US. Pat. No 3,676,007, by Raymond W. Kiess, which is in turn a continuation-in-part of Ser. No. 692,525, filed Dec. 21, 1967, now US. Pat. No. 3,561,878 of Raymond W. Kiess, patented Feb. 9, 1971.

This application is a continuation-in-part of copending application Ser. No. 224,457, filed Feb. 8, 1972, of Raymond W. Kiess and Peter H. Stewart, which in turn is a continuation-in-part of Ser. No. 1 13,881, filed Feb. 9, 1971, now U.S. Pat. No. 3,676,007, of Raymond W. Kiess and which in turn is a continuation-in-part of application Ser. No. 692,525, filed Dec. 21, 1967, now US. Pat. No. 3,561,878, of Raymond W. Kiess, patented Feb. 9, 1971.

This invention relates to the chemical quantitation or quantitative analysis of certain constituents present in blood, urine and other body fluids that are of significant interest to the medical and health professions, for the detection of pathological conditions of the human or animal bodies and also as a guide to dictate therapy as well as serving as a parameter to judge prognostically as to the state of health or morbidity of the organism.

Procedural simplification from a viewpoint of chemical analysis, as well as instrumentation, has resulted as the development of the state of the art has progressed.

Simply stated, biochemical colorimetry is based upon the measurement of color developed by certain chemical reactions, the color developed usually being stoichiometrically related to the concentration of the constituent being analyzed.

In the early years of biological or clinical chemistry, the colors developed in a chemical reaction were compared visually with those of known concentrations. Thus, the unknown constituents could be approximated and the results could even be interpolated in certain instances.

The twin-cup type visual colorimeter followed and a split-field comparator was used to indicate an approximation of color equilibrium, the concentration being related to the relative depts of immersion of the optical probes.

Later, a filter photometer evolved which used a filter to isolate the useable and desired portion of the spectrum, and later prisms, diffraction gratings and interference filters were introduced, all of which greatly increased the sensitivity, specificity, reproducibility, and accuracy of the procedure. It also removed the human element from matching colors visually.

Other instruments also evolved utilizing the ultraviolet and infra-red portions of the spectrum.

As the state of the art progressed, different chemical formulations of reagents which were more specific and possed more desirable stability characteristics were developed. Until this stage was reached, different batches to reagents had to be tested and graphs constructed to relate color development to terms of concentration.

The art has now evolved to the point thatcolorimeter or spectrophotometer scales can be directly calibrated to be read in terms of concentration, rather than to take a reading from the meter and refer to a calibration table, or graph, to relate this reading to meaningful terms of concentration. Methods have also been introduced whereby a single calibrated meter with a keying mechanism can be inserted in a colorimeter, thus making certain that the appropriate filter is properly positioned in the light beam or, several scales can be inscribed on the meter face with no provision made for the changing of filters.

It is quite apparent that the first of the two approaches mentioned in the provision paragraph has the limitation of cost because a separate meter movement must be used for each particular test, as well as being awkward and cumbersome and, that the latter approach is limited because of physical limitations as to the number of arcs capable of being inscribed thereon are limited to four or five, and the lack of any provision for selecting the proper filter.

The present invention relates to a direct reading colorimeter and describes apparatus that will allow the selection of a suitable scale in terms of the constituent to be quantitated, as well as the selection of an appropriate filter, in a simple and reliable manner so as to leave no opportunity for error.

This invention further relates to colorimetric body fluid constituent concentration analyzing means in combination with blood prothrombin test analyzing means and more particularly, to such analyzing means of the direct digital reading, self-referencing photometric type.

It is an object of this invention to provide a new and novel colorimetric blood analyzer and prothrombin analyzer having optimum test accuracy heretofore unattainable in the art.

It is another object of the present invention to provide a new and novel colorimetric blood analyzer and prothrombin analyzer which is readily adapted to relatively low cost manually processed instruments for use in doctors offices and small volume applications in laboratories and hospitals.

Still another object of the present invention is to provide a new and novel colorimetric blood analyzer and prothrombin analyzer comprised of a plurality of interchangeable modules, each such module being adapted for a specific blood test, whereby a particular instrument embodying the invention can be selectively adapted to any given group of such tests.

Still another object of the present invention is to provide a new and novel colorimetric blood analyzer and prothrombin analyzer comprised of a plurality of inter changeable modules, each such module being adapted for a specific blood test, whereby a particular instrument embodying the invention can be selectively adapted to any given group of such tests; and wherein each said module programs the said instrument for the appropriate light wavelength, reagent blank offset, scale factor and calibration parameters to allow direct display of the desired blood constituent concentration units being tested on a common readout instrumentality in a numerical or digital format.

Yet another object of the present invention is to provide a new and novel colorimetric blood analyzer and prothrombin analyzer which is self-referencing for each and every constituent test performed thereby.

Yet another object of the present invention is to provide a new and novel colorimetric blood analyzer and prothrombin analyzer, including selective transmittance filter means, wherein each test function can be selectively adjusted to compensate for variable total energy transmittance through said filter means.

Yet another object of the present invention is to provide a new and novel colorimetric blood analyzer and prothrombin analyzer, including means selectively illuminating blood samples and associated diagnostic reagents through selective transmittance filter means, wherein each test function can be selectively adjusted, in the field, for such test variables as occur between different lots and ages of diagnostic reagents and variations in filter parameters such as the spectral characteristics of center wavelength, bandwidth, and the like.

These and other objects of the present invention will become more fully apparent with reference to the following specification and drawings, which relate to a preferred embodiment of the present invention together with those embodiments from the aboveidentified prior patents of Raymond W. Kiess by way of background for the invention.

In the drawings:

FIG. 1 is a diagrammatic representation of the basic components of a photometer spectrophotometer;

FIG. 2 is an isometric view of a preferred form of colorimeter construction in accordance with the teachings of the present invention;

FIG. 3 is a cross-sectional elevation of the device of FIG. 2 taken on the line 3 3 of FIG. 4;

FIG. 4 is a cross-section taken on the line 4 4 of FIG. 3;

FIG. 5 is a fragmentary view of an enlarged scale of the camming mechanism use for shifting the filter means;

FIG. 6 is a perspective of another embodiment of the invention as described in US. Pat. No. 3,676,007 of Raymond W. Kiess;

FIG. 7 is a front plan view of the embodiment of FIG. 6, with the cover broken away, showing the coordinated assembly of scales, filters and indicating means thereof;

FIG. 8 is a cross-section taken along line 8 8 of FIG. 7;

FIG. 9 is a cross-section taken along line 9 9 of FIG. 7;

FIG. 10 is a schematic circuit diagram for the embodiment of FIGS. 6 9;

FIG. 11 is a perspective of another embodiment of the present invention in which each filter is coordinated with a plurality of circuit means adapted to normalize a single readout means to the units of each test being performed;

FIG. 12 is a block diagram of a normalizing circuit means associated with the structure of FIG. 11;

FIG. 13 is a top perspective of a test console in a preferred embodiment of a normalized testing means providing a multiplicity of constituent concentration and a prothrombin time tests all normalized to a single readout device;

FIG. 14 is a top plan view of the console of FIG. 13 partially broken away to show a portion of the interior of the console;

FIG. 15A is a front plan view of a test function module of the present invention;

FIG. 15B is a back plan view of the test function module of FIG. 15A, illustrating its interconnection with the test console of FIGS. 13 and l4;

FIG. 15C is a side elevation of a main test cavity structure of the present invention as generally shown in FIGS. 13 and 14;

FIG. ISD is a top plan view of a test cavity;

FIG. 15E is a bottom plan view of FIG. 15C;

FIG. 15F is a side elevation of the structure of FIG. 15C rotated FIG. 15G is a cross-section taken along line 15G lSG of FIG. 15F;

FIG. lSI-I is a side elevation of the main test cavity of the present invention rotated from the view shown in FIG. 15C;

FIG. 15I is an enlarged detail of the main test photodetector and the manner in which it is affixed to the test cavity structure of FIGS. 15C through 15H; and

FIG. 15] is a side elevation of a typical microswitch structure of the present invention;

FIG. 16 is a block diagram of the normaling testing system contained in the test console of FIGS. 13 and 14;

FIG. 17 is a circuit schematic of a preferred embodiment of the photocell preamplifier and log converter circuits of the present invention for constituent concentration analysis;

FIG. 18 is a graphic representation of the voltage output functions and timing interval resulting therefrom relating to the log converter circuit of FIG. 17;

FIG. 19 is a graphic illustration of the concentration line functions of the system of FIGS. 16 and 17;

FIG. 20 is a schematic diagram of the main control circuit generally illustrated in FIG. 16;

FIG. 21 is a schematic circuit diagram of the prothrombin time circuit generally illustrated in FIG. 16;

FIG. 22 is a circuit schematic of a preferred commercial embodiment of the photodetector preamplifier generally illustrated in FIG. 16;

FIG. 23 is a schematic circuit diagram of the counting, driver-decoder and display circuits generally illustrated in FIG. 16;

FIG. 24 is a schematic diagram of the switching matrix and its association with the balance of the system and individual test function modules generally illustrated in FIG. 16;

FIG. 25 is a graphic representation of concentration versus absorbance for constituent concentration tests having negative slope characteristics;

FIG. 26 is a more detailed schematic of the filter wheel servo control circuit 228 generally shown in FIG. 16;

FIG. 27 is a more detailed schematic circuit diagram of the incubator heat control circuit generally shown in FIG. 16;

FIG. 28 is a perspective of a test function module of the present invention in which provision is made for adjustment of the test function parameters to compensate for energy and spectral transmittance variables in the selective transmittance filters of the invention as well as for variations in the characteristics of diagnostic reagents and the like;

FIG. 29 is a top perspective of a test console of the present invention with a cover member in place, the latter providing access to certain variable components of the test modules to permit in-field compensating adjustments of each module; and

FIG. 30 is a cross-section taken along line Y Y of FIG. 29. 

1. In direct reading digital filter photometers for use in performing a plurality of chemical analyses of liquid samples, wherein the concentration of a specific constituent of a sample for each particular analysis is proportional to the intensity of radiant energy of a particular frequency range transmitted through a sample, the combination including: a source of radiant energy; filter means for isolating a particular frequency range of radiant energy emitted from said source; transducer means positioned to be responsive to said filtered radiant energy from said source and for generating a signal proportional to the intensity of said filtered radiant energy; receptacle means for supporting a cuvette containing sample liquid to be analyzed in said path of radiant energy; electrical digital readout means for providing a readout as a function of the intensity of said received radiant energy; analog-digital computing circuit means for deriving and generating a signal proportional to the concentration of said constituent to be analyzed in said liquid; assembly means comprising a plurality of electrical normalizing means comprising calibrated reference parameters for each constituent test, and a plurality of associated individual filter means; each of said normalizing means being selectively electronically connectable with said computing circuit means for providing electrical reference parameters for said computing circuit means for constraining said readout means to provide a direct digital readout of the concentration of a specific constituent related to a particular analysis in response to the intensity of radiant intensity received from said source through a particular one of said filter means, each of said normalizing means being selectively connected with a particular one of said filter means; and correlating means for selectively correlating said normalizing means with said readout means and said filter means for performing each said particular analysis. wherein said normalizing means include adjustable means for constraining said transducer means to respond to transmitted illumination through said individual filter means in the absence of said sample liquid in said path as if the total radiant energy transmitted by each said filter means is of substantially equal magnitude.
 2. The invention defined in claim 1, wherein said normalizing means further includes compensating means selectively adjustable to vary said reference parameters to compensate for parametric variations in said sample liquids and variations in the spectral characteristics of said filter means.
 3. The invention defined in claim 1, wherein said normalizing means comprises a plurality of circuit modules, each including a given set of said reference parameters peculiar to a given analysis to be perFormed and selectively interconnected with said correlating means to effect a particular analysis; said adjustable means being comprised of at least one of said reference parameters in each said module the said one of said reference parameters being variable in magnitude.
 4. The invention defined in claim 3, wherein said normalizing means further includes compensating means selectively adjustable to vary other of said reference parameters to compensate for parametric variations in said sample liquids and variations in the spectral characteristics of said filter means.
 5. In a direct reading filter photometer for performing a plurality of chemical analyses of liquid samples irradiated by light of preselected wavelengths, including constituent concentration and prothrombin time analyses, the combination comprising: detector means responsive to the intensity of light transmitted through said samples and for providing outputs representative of said constituent concentration and prothrombin time values; converter means for converting said outputs to digital signals representative thereof; and display means for receiving said digital signals and converting same to direct numerical readouts of said constituent concentrations and prothrombin times; and adjustable compensating means for selectively varying the response characteristics of said detector means to compensate for variations in the transmittance characteristics of said liquid samples, the spectral characteristics of said transmitted light and the total energy of said light irradiating said samples throughout the spectrum of said preselected wavelengths.
 6. Testing means determining a particular constituent concentration in a liquid test sample irradiated by light of a preselected wave length comprising; a cavity for receiving a liquid test sample having a light path therethrough; detector means for receiving light transmitted through said cavity with and without a liquid sample contained therein and providing first and second current signals proportional to the intensity of said transmitted light through an open and sample containing cavity, respectively; amplifier means for receiving and converting said first current signal to a first output voltage representative of the light transmittance of said open cavity at a first conversion gain and receiving and converting said second current signal to a second output voltage representative of the light transmittance through said test sample at a second conversion gain, said gains having respective values such that said amplifier will produce equal output voltages for said open cavity and for the presence of a standard sample reagent blank in said cavity in place of said test sample; converter means for receiving and converting said first and second output voltages to first and second time intervals, respectively, said time intervals being proportional to the respective logarithms of said first and second output voltages; reference clock means; counter means; and control means interconnected with said converter means, said reference clock means and said counter means enabling said converter means to initiate said time intervals and gating said clock means into said counter means at the beginning of and throughout said time intervals; said control means including selecting means for constraining said counter to count to opposite directions over said first and second time intervals, to subtract one count from the other, whereby the difference in the said counts is representative of the said particular constituent concentration in said test sample; and wherein said amplifier means includes compensating means for selectively varying said first conversion gain to compensate for variations in the transmittance of total light energy through said open cavity at various preselected wavelengths to maintain said first output voltage substantially uniform throughout a spectrum of selected wavelengths.
 7. The invention defined in claim 6, wherein said amplifier means further includes second compensating means for selectively varying said second conversion gain to compensate for variations in the transmittance characteristics of said standard sample reagent blank.
 8. The invention defined in claim 6, wherein said reference clock means comprises a variable frequency oscillator; and wherein said testing means further comprises correlating means for constraining said oscillator to a particular clock frequency for each particular constituent concentration test performed by said testing means; said correlating means further including frequency compensating means for selectively varying said particular clock frequency to compensate for spectral variations in said light transmitted through said cavity.
 9. The invention defined in claim 7, wherein said reference clock means comprises a variable frequency oscillator; and wherein said testing means further comprises correlating means constraining said oscillator to a particular clock frequency for each particular constituent concentration test performed by said testing means; said correlating means further including frequency compensating means selectively varying said particular clock frequency to compensate for spectral variations in said light transmitted through said cavity.
 10. Testing means determining a particular constituent concentration in a liquid test sample irradiated by light of a preselected wave length comprising: a cavity for receiving a liquid test sample having a light path therethrough; detector means for receiving light transmitted through said cavity with and without a liquid sample contained therein and providing first and second current signals proportional to the intensity of said transmitted light through an open and sample containing cavity, respectively; amplifier means for receiving and converting said first current signal to a first output voltage representative of the light transmittance of said open cavity at a first conversion gain and for receiving and converting said second current signal to a second output voltage representative of the light transmittance through said test sample at a second conversion gain, said gains having respective values such that said amplifier will produce equal output voltages for said open cavity and for the presence of a standard sample reagent blank in said cavity in place of said test sample; converter means for receiving and converting said first and second output voltages to first and second digital signals, respectively; and computer means for receiving and determining the difference in magnitude of said digital signals; said difference representing the particular constituent concentration in said test sample; and wherein said amplifier means includes manually adjustable compensating means selectively varying said first conversion gain to compensate for variations in the transmittance of total light energy through said open cavity at various preselected wavelengths to maintain said first output voltage substantially uniform throughout a spectrum of selected wavelengths.
 11. The invention defined in claim 10, wherein said amplifier means further includes second manually adjustable compensating means for selectively varying said second conversion gain to compensate for variations in the transmittance characteristics of said standard sample reagent blank.
 12. Testing means determining a particular constituent concentration in a liquid test sample irradiated by light of a preselected wave length comprising: a cavity for receiving a liquid test sample having a light path therethrough; detector means for receiving light transmitted through said cavity with and without a liquid sample contained therein and providing first and second current signals proportional to the intensity of said transmitted light through an open and sample containing cavity, respectively; amplifier means for receiving and converting said first current signal to a first output voltage representative of the light transmittance of said open cavity at a first conversion gain and for receiving and converting said second current signal to a second output voltage representative of the light transmittance through said test sample at a second conversion gain, said gains having respective values such that said amplifier will produce equal output voltages for said open cavity and for the presence of a standard sample reagent blank in said cavity in place of said test sample; converter means for receiving and converting said first and second output voltages to first and second digital signals, respectively; computer means for receiving and determining the difference in magnitude of said digital signals; said difference representing the particular constituent concentration in said test sample; said testing means further includes a reference circuit module for each test to be performed, each said module including circuit means for defining a plurality of standard reference parameters peculiar to the test to which said module relates; and switching means selectively interconnecting said modules with said amplifier means and said converter means such that said standard reference parameters constrain said amplifier means and said converter means to modify said gain values and said digital signals and thereby normalize said testing means to the specific test being performed; said standard reference parameters being selectively variable to compensate for variations in the spectral characteristics of said transmitted light and the transmittance characteristics of the said standard sample reagent blank for each said specific test and to provide substantially uniform response in each said test of said amplifier means to said open cavity over the spectrum of said preselected wavelengths. 